Since the advent of the biotechnology revolution, there has been a desire to grow cells in culture and a need to separate components in these fluid systems. Such separation has been accomplished by a multitude of methods, including, for example, through centrifugation, ion exchange columns, and physical filtering, among many others.
Bioreactors, which are typically chambers in which a cell culture is grown, have been produced in many forms. Frequently, bioreactors are used to grow a mammalian cell culture in which the cells produce an extracellular component, such as an antibody or recombinant protein. Bioreactors are also used for virus production. A separation process is performed in order to concentrate and purify the desired component from the bioreactor, which may, for example, be useful as a therapeutic or diagnostic agent.
One bioreactor configuration uses an impeller to constantly mix a liquid growth medium that has been inoculated with a cell culture. Ports in the bioreactor allow for nutrients to be added, contents to be removed, and sensing of various growth parameters, such as dissolved oxygen content and pH. In batch systems the growing culture is allowed to grow to a point at which the desired component is believed to be at optimal concentration, and then the entire vessel is harvested to separate the cells from the medium for secreted products. This separation is typically done by filtration or centrifugation. In contrast to batch systems, in a perfusion bioreactor, at some point after culture inoculation, the liquid media is circulated out of the bioreactor, through a separation device, and then returned to the bioreactor. The separation device is typically a filtration device, centrifuge, or a settling device. The separation device selectively removes a percentage of the contents, including any secreted product and cell waste product, of the liquid stream from the bioreactor. The volume removed is replaced to the bioreactor with growth medium. In these types of systems, separation can occur for an extended period of time, as long as wastes are removed and the culture medium is replenished, as needed.
With either of these batch or perfusion systems, however, the complexity of the systems and the frequent requirement to sterilize parts before use and thoroughly clean after use adds to the overall cost and reduces the efficiency of the cell culture production and filtration process. There is therefore a need in the art for bioreactors, bioreactor systems, and filtration devices that allow for the efficient production of biological components from a cell culture.
A recent technology for biological filtration involves the use of hollow fiber technology. Hollow fiber filters typically have a plurality of relatively thin, fiber tubes that are arranged in parallel to one another. A fluid having at least one biological component is passed through the wall of the tubes, which are designed to allow for the passage of very small components, along with the fluid from the vessel. The fluid and components that are small enough to pass through the hollow fiber wall of a specified size is then collected. The fluid that passes through, either with or without the desired biological component, is present in a more pure form relative to the starting fluid. This filtration process is made significantly more efficient by the flowing of the liquid medium that occurs along the walls of the hollow fibers. The flow of that liquid causes the constant removal of material from the inner walls of the fiber tubes that would otherwise quickly clog the fibers and prevent filtration.
Hollow fiber filtration can be used to filter many types of biological components. A very common system that employs hollow fiber filtration utilizes a bioreactor.